Autoimmune Diseases and Serum Autoantibodies in NCWS and IBS Patients

Autoimmune Diseases and Serum Autoantibodies in Non-celiac Wheat Sensitivity Patients in Comparison to IBS Patients

In recent years, a new gluten- or wheat-related disease has emerged, a condition labelled "non-celiac gluten sensitivity" (NCGS) or "non-celiac wheat sensitivity" (NCWS). Given the lack of a diagnostic biomarker, NCGS/NCWS mostly remains a diagnosis of exclusion, especially respect to CD and WA, so a confirmatory test is required. The Salerno experts suggested the double-blind, placebo-controlled (DBPC), cross-over, gluten/wheat challenge as the gold standard test to discriminate true NCGS/NCWS patients. There are conflicting data about the real mechanisms which induce symptoms in NCGS/NCWS patients after wheat ingestion. Some Authors suggested a prevalent role for Fermentable Oligosaccharides-Disaccharides-Monosaccharides and Polyols (FODMAPs), rather than gluten in determining the symptoms. Other studies underlined the activation of mechanisms of both innate and acquired immunity in NCWS patients, after wheat ingestion. In the present study, we included a group of consecutive NCWS patients, diagnosed with DBPC wheat challenge, to evaluate a) the frequency of autoimmune diseases, b) the frequency and pattern of serum ANA and other non-organ-specific and/or organ-specific autoantibodies, and c) the possible correlations between autoimmune diseases and serum autoantibodies presence and other NCWS-related disease characteristics, in comparison with age- and sex- matched healthy blood donors and IBS patients unrelated to NCWS.

Study Overview

• Status: Completed
• Conditions: Non-celiac Wheat Sensitivity; Non-celiac Gluten Sensitivity

Detailed Description

In recent years, a new gluten- or wheat-related disease has emerged, a condition labelled "non-celiac gluten sensitivity" (NCGS) or "non-celiac wheat sensitivity" (NCWS). This is very often a self-reported condition, since patients refer to intestinal (mainly irritable bowel syndrome (IBS)-like) and/or extra-intestinal symptoms (i.e. fatigue, headache) caused by gluten or wheat ingestion, even though they do not have celiac disease (CD) or wheat allergy (WA). Given the lack of a diagnostic biomarker, NCGS/NCWS mostly remains a diagnosis of exclusion, especially respect to CD and WA, so a confirmatory test is required. The Salerno experts suggested the double-blind, placebo-controlled (DBPC), cross-over, gluten/wheat challenge as the gold standard test to discriminate true NCGS/NCWS patients.

However, there are conflicting data about the real mechanisms which induce symptoms in NCGS/NCWS patients after wheat ingestion. Some Authors suggested a prevalent role for Fermentable Oligosaccharides-Disaccharides-Monosaccharides and Polyols (FODMAPs), rather than gluten in determining the symptoms. Other studies underlined the activation of mechanisms of both innate and acquired immunity in NCWS patients, after wheat ingestion. In line with the evidence of an immunologic activation in NCWS, we showed in a previous study that about one quarter of NCWS patients suffered from associated autoimmune diseases (mainly Hashimoto's thyroiditis), compared with a smaller proportion of a control group including IBS patients (about 3%). Furthermore, we showed that serum samples of NCWS patients tested positive for anti-nuclear (ANA) in more than one third of the cases. However, that study included mainly patients evaluated in a retrospective manner and no other autoantibodies were evaluated apart from ANA.

In the present study, we included a group of consecutive NCWS patients, diagnosed with DBPC wheat challenge, to evaluate a) the frequency of autoimmune diseases, b) the frequency and pattern of serum ANA and other non-organ-specific and/or organ-specific autoantibodies, and c) the possible correlations between autoimmune diseases and serum autoantibodies presence and other NCWS-related disease characteristics, in comparison with age- and sex- matched healthy blood donors and IBS patients unrelated to NCWS.

• Study Type: Observational
• Enrollment (Actual): 58

Contacts and Locations

Study Locations

• Italy
  • Palermo, Italy, 90129
    • Department of Internal Medicine, University Hospital of Palermo
  • Agrigento
    • Sciacca, Agrigento, Italy, 92019
      • Department of Internal Medicine, Giovanni Paolo II Hospital of Sciacca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

We prospectively surveyed 58 adult patients with a definitive diagnosis of NCWS, based on DBPC wheat challenge, most of them suffering from IBS-like-clinical presentation, according to Rome IV criteria. The patients were consecutively recruited between January 2016 and October 2017 at the outpatient clinics of the Department of Internal Medicine of the University Hospital of Palermo and the Department of Internal Medicine of the Hospital of Sciacca (both in southern Italy). Two control groups were selected. One included 76 consecutive healthy blood donors sex- (+ 5%) and age-matched (+ 2 years) with the NCWS patients, while the second included 55 patients with a diagnosis of IBS unrelated to NCWS or other types of food "intolerance/allergy", who were consecutively recruited during the study period and sex- (+ 5%) and age-matched (+ 2 years) with the NCWS patients.

Description

NCWS

Inclusion criteria:

• resolution of symptoms on a standard elimination diet, without wheat, cow's milk, yeast, and other food(s) causing self-reported symptoms
• symptom reappearance on a DBPC wheat challenge. As in previous studies, a DBPC cow's milk protein challenge and other open food challenges were also performed
• age above 18 years and <65 years
• follow-up duration longer than 12 months after the initial diagnosis
• at least two outpatient visits during the follow-up period.

Exclusion criteria:

• positive serum assays for celiac disease (i.e. anti-tissue transglutaminase (anti-tTG) IgA and anti-deamidated gliadin peptides (anti-DGP) IgG antibodies)
• presence of intestinal villous atrophy, documented in all the patients carrying the DQ2 and/or the DQ8 HLA haplotypes
• positive IgE-mediated immune-allergy tests to wheat (skin prick tests and/or specific serum IgE detection).

IBS IBS diagnosis had been made in accordance with the Rome IV criteria and none of these patients improved on an elimination diet without wheat, cow's milk, egg, tomato or chocolate.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
NCGS/NCWS patients; Adult patients with a definitive diagnosis of NCWS, based on DBPC wheat challenge, most of them suffering from IBS-like-clinical presentation, according to Rome IV criteria. The patients were consecutively recruited between January 2016 and October 2017 at the outpatient clinics of the Department of Internal Medicine of the University Hospital of Palermo and the Department of Internal Medicine of the Hospital of Sciacca (both in southern Italy)
Heathy blood donors; Consecutive healthy blood donors sex- (+ 5%) and age-matched (+ 2 years) with the NCWS patients.
IBS patients; Consecutive patients with a diagnosis of IBS unrelated to NCWS or other types of food "intolerance/allergy", who were consecutively recruited during the study period and sex- (+ 5%) and age-matched (+ 2 years) with the NCWS patients.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of associated autoimmune diseases	The presence of autoimmune disorders both in NCWS and IBS control patients was evaluated by a structured questionnaire and a review of patients' clinical records. The presence of one of the following was looked for in all subjects: connective tissue diseases, autoimmune endocrinological diseases, autoimmune hepatitis, primary biliary cirrhosis, epilepsy with cerebral calcification, unexplained cerebellar ataxia, alopecia, psoriasis, atrophic autoimmune gastritis, and immune anemia, neutropenia, or thrombocytopenia.	22 months
Serum autoantibodies	The frequency, titers and patterns of serum ANA, antibodies against double stranded DNA (anti-dsDNA), extractable nuclear antigen (ENA), islet cells of the pancreas (ICA), parietal cell antibodies (APCA), and, finally, tireoglobulin (anti-TG) and thyroid peroxidase (anti-TPO) were evaluated by ELISA and Immunofluorescence.	22 months
Clinical characteristics of NCWS and IBS patients	Frequency of autoimmune diseases and autoantibodies were correlated with the following clinical and laboratory parameters: age at diagnosis, gender, coexistent pathologies, atopic diseases and nickel allergy, anemia, coexistent other food allergies, presence of IBS-like symptoms, functional dyspepsia, and extraintestinal symptoms, BMI, duodenal histology lesions, and DQ2/DQ8 HLA haplotypes.	22 months

Collaborators and Investigators

• Sponsor: University of Palermo

Publications and helpful links

General Publications

• Mansueto P, Seidita A, D'Alcamo A, Carroccio A. Non-celiac gluten sensitivity: literature review. J Am Coll Nutr. 2014;33(1):39-54. doi: 10.1080/07315724.2014.869996.
• Carroccio A, Mansueto P, Iacono G, Soresi M, D'Alcamo A, Cavataio F, Brusca I, Florena AM, Ambrosiano G, Seidita A, Pirrone G, Rini GB. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol. 2012 Dec;107(12):1898-906; quiz 1907. doi: 10.1038/ajg.2012.236. Epub 2012 Jul 24.
• Carroccio A, Rini G, Mansueto P. Non-celiac wheat sensitivity is a more appropriate label than non-celiac gluten sensitivity. Gastroenterology. 2014 Jan;146(1):320-1. doi: 10.1053/j.gastro.2013.08.061. Epub 2013 Nov 22. No abstract available.
• Carroccio A, Mansueto P, D'Alcamo A, Iacono G. Non-celiac wheat sensitivity as an allergic condition: personal experience and narrative review. Am J Gastroenterol. 2013 Dec;108(12):1845-52; quiz 1853. doi: 10.1038/ajg.2013.353. Epub 2013 Nov 5.
• Carroccio A, D'Alcamo A, Cavataio F, Soresi M, Seidita A, Sciume C, Geraci G, Iacono G, Mansueto P. High Proportions of People With Nonceliac Wheat Sensitivity Have Autoimmune Disease or Antinuclear Antibodies. Gastroenterology. 2015 Sep;149(3):596-603.e1. doi: 10.1053/j.gastro.2015.05.040. Epub 2015 May 27.
• Catassi C, Elli L, Bonaz B, Bouma G, Carroccio A, Castillejo G, Cellier C, Cristofori F, de Magistris L, Dolinsek J, Dieterich W, Francavilla R, Hadjivassiliou M, Holtmeier W, Korner U, Leffler DA, Lundin KE, Mazzarella G, Mulder CJ, Pellegrini N, Rostami K, Sanders D, Skodje GI, Schuppan D, Ullrich R, Volta U, Williams M, Zevallos VF, Zopf Y, Fasano A. Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts' Criteria. Nutrients. 2015 Jun 18;7(6):4966-77. doi: 10.3390/nu7064966.
• Di Liberto D, Mansueto P, D'Alcamo A, Lo Pizzo M, Lo Presti E, Geraci G, Fayer F, Guggino G, Iacono G, Dieli F, Carroccio A. Predominance of Type 1 Innate Lymphoid Cells in the Rectal Mucosa of Patients With Non-Celiac Wheat Sensitivity: Reversal After a Wheat-Free Diet. Clin Transl Gastroenterol. 2016 Jul 7;7(7):e178. doi: 10.1038/ctg.2016.35.
• Drossman DA. Functional Gastrointestinal Disorders: History, Pathophysiology, Clinical Features and Rome IV. Gastroenterology. 2016 Feb 19:S0016-5085(16)00223-7. doi: 10.1053/j.gastro.2016.02.032. Online ahead of print.
• Losurdo G, Principi M, Iannone A, Giangaspero A, Piscitelli D, Ierardi E, Di Leo A, Barone M. Predictivity of Autoimmune Stigmata for Gluten Sensitivity in Subjects with Microscopic Enteritis: A Retrospective Study. Nutrients. 2018 Dec 18;10(12):2001. doi: 10.3390/nu10122001.
• Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, Kaukinen K, Rostami K, Sanders DS, Schumann M, Ullrich R, Villalta D, Volta U, Catassi C, Fasano A. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012 Feb 7;10:13. doi: 10.1186/1741-7015-10-13.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): January 1, 2017
• Study Completion (Actual): October 30, 2018

Study Registration Dates

• First Submitted: August 31, 2019
• First Submitted That Met QC Criteria: August 31, 2019
• First Posted (Actual): September 4, 2019

Study Record Updates

• Last Update Posted (Actual): April 20, 2020
• Last Update Submitted That Met QC Criteria: April 17, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity; Autoimmune Diseases
• Other Study ID Numbers: ACPM22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No